Acute lipopolysaccharide exposure facilitates epileptiform activity via enhanced excitatory synaptic transmission and neuronal excitability in vitro
Neuropsychiatric Disease and Treatment
a cute lipopolysaccharide exposure facilitates epileptiform activity via enhanced excitatory synaptic transmission and neuronal excitability in vitro
Wen Jiang 2
0 college of life sciences, shaanxi Normal University , Xi'an 710062, People's republic of china
1 Department of Neurology, First a ffiliated h ospital of Xi'an Medical University , Xi'an 710077, People's republic of china
2 Department of Neurology, Xijing hospital, Fourth Military Medical University , Xi'an 710032, People's republic of china
Growing evidence indicates brain inflammation has been involved in the genesis of seizures. However, the direct effect of acute inflammation on neuronal circuits is not well known. Lipopolysaccharide (LPS) has been used extensively to stimulate brain inflammatory responses both in vivo and in vitro. Here, we observed the contribution of inflammation induced by 10 μg/mL LPS to the excitability of neuronal circuits in acute hippocampal slices. When slices were incubated with LPS for 30 minutes, significant increased concentration of tumor necrosis factor α and interleukin 1β were detected by enzyme-linked immunosorbent assay. In electrophysiological recordings, we found that frequency of epileptiform discharges and spikes per burst increased 30 minutes after LPS application. LPS enhanced evoked excitatory postsynaptic currents but did not modify evoked inhibitory postsynaptic currents. In addition, exposure to LPS enhanced the excitability of CA1 pyramidal neurons, as demonstrated by a decrease in rheobase and an increase in action potential frequency elicited by depolarizing current injection. Our observations suggest that acute inflammation induced by LPS facilitates epileptiform activity in vitro and that enhancement of excitatory synaptic transmission and neuronal excitability may contribute to this facilitation. These results may provide new clues for treating seizures associated with brain inflammatory disease.
lipopolysaccharide; hippocampus; inflammation; epileptiform activity; synaptic
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open access to scientific and medical research
O r i g i N a l r e s e a r c h
Introduction
Brain injuries such as trauma, stroke, and infection are often associated with acute
occurrence of seizures.1,2 Although the underlying mechanism remains unclear,
accumulating clinical and experimental evidence has suggested that inflammatory processes
involved in these injuries may contribute to the genesis of seizures.3 Traditionally, the
brain has been considered an immunoprivileged organ because of the presence of the
blood–brain barrier and the lack of a conventional lymphatic system. Nevertheless,
both the innate and adaptive immune responses are readily evoked within the brain after
varied injuries. Resident cells in brain parenchyma such as microglia, astrocytes, and
neurons can respond to these stimuli and create inflammatory molecules. In addition,
peripheral immune cells extravasating from cerebral vascular can also produce
inflammatory media and aggravate inflammatory surroundings.4 These inflammatory
mediators, including tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), nitric oxide
(NO), and reactive oxygen species, are reported to increase cellular excitability.5–7
In animal experiments, lipopolysaccharide (LPS), a major component of the outer
membrane of gram-negative bacteria, has been used extensively in investigating
mechanisms of brain inflammation both in vivo and in vitro. Mainly in microglia,8 by
the stimulation of toll-like receptor 4 LPS results in the
induction of transcriptional factors such as nuclear factor κB, which
trigger various proinflammatory genes such as those encoding
cytokines, chemokines, proteins of the complement system,
and inducible nitric oxide.9,10 Furthermore, LPS induces a
rapid glutamate (a major excitatory neurotransmitter in brain)
018 release in rat cortex slices, which may lead to an imbalance
l-u2 between excitation and inhibition in the neuronal circuit.11
-J21 In vivo, previous studies showed that LPS intraperitoneal or
no intracerebroventricular injection enhanced seizure
susceptibil.027 ity through increasing IL-1β, cyclooxygenase 2, NO, or
pros.496 taglandins in different epilepsy models.12–15 However, little is
.573 known about the direct effects of the acute application of LPS
/yb on epileptiform activity, synaptic strength, and neuronal
excitcom ability in vitro and the possible underlying mechanisms.
.sse In the electrophysiology of seizure, an imbalance between
rvpe excitation and inhibition is thought to mediate seizure
activ.d . ity. Increased excitation and/or decreased inhibition can
o
w ly
/ww no induce the initiation of a seizure. Neuronal excitability and
/:ttsp lseu synaptic transmission are both involved in maintaining this
h an balance.16,17 Therefore, in the present study, we focused on
from rsoe the effects of acute inflammation induced by LPS on the
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